Derivatives of triazole, methods for their preparation, pharmaceutical composition, method of treatment or prevention of fungal infections, the intermediate product

 

(57) Abstract:

Describes compounds of formula (I) R1-OP(O)(OH)2where R1represents a group of formula Ia, in which R2represents phenyl substituted by one or more halogen atoms; R3represents N or CH3; R3arepresents H or, together with R3may submit =CH2; and R4represents 5 - or 6-membered nitrogen-containing heterocyclic ring, which is arbitrarily substituted with one group or more selected from halogen, =O, phenyl [substituted by a group selected from CN and (C6H4)-OCH2CF2CHF2] or CH= CH(C6H4)OCH2CF2F2; or phenyl substituted by one or more groups selected from halogen and methylpyrazole, or its pharmaceutically acceptable salt. The above triazole derivatives can be used in therapy, in particular for the treatment of fungal infections of humans and other mammals. Also describes the methods for their preparation, pharmaceutical composition, method of treatment or prevention of fungal infections and the intermediate product. 6 C. and 4 h.p. f-crystals, 2 ill., 3 table.

This invention relates to dei and other mammals), the method of their application, containing drugs and methods for their preparation.

There are a large number of antifungal compounds of the triazole. For example, in European patent application 0440372, example 7 described (2R,3S)-2-(2,4-differenl)-3-(5-fluoro-4 - pyrimidinyl)-1-(1H-1,2,4-triazole-1 - yl)butane-2-ol (also known as voriconazole), which has a particularly good activity against the clinically important fungi Aspergillus spp. However, this compound has a low solubility in water, which makes necessary the use of complexing agents to obtain a satisfactory water drugs such as drugs for intravenous injection. In European patent application 0440372 offer joint products with derivatives of cyclodextrin to improve solubility; however, it is always desirable to reduce the number of components in the product to a minimum to minimize potential adverse reactions in patients.

In a patent application in the UK 2128193 described esters of phosphoric acid for use as fungicides and insecticides plants.

Maurine and other [Int. J. Pharm, 1993, 94 (1- 3), 11-14] describe bismesylate -(2,4-differenl)- - [(l-(2-(3 - pyridyl)phenylalanyl)]-1H-1,2,4-triazole-1-ethanol, which, like everyboby means known from European patent application 0576201 and International patent application WO 97/01552.

In European patent application 0413674 described receiving prodrugs of therapeutic inhibitors of glycosidase by phosphorylation of the free hydroxyl group of this molecule. However, phosphorylation of tertiary hydroxyl groups is not described.

At the present time found that the antifungal compounds of the triazole type compounds containing a tertiary hydroxyl group, including (2R, 3S)-2-(2, 4-differenl)-3-(5 - fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazole-1-yl)-butane-2 - ol, can be converted into prodrugs with greater solubility, which are easily converted in vivo, giving the desired active radical.

According to this invention proposed a compound of the formula

R1-OP(O)(OH)2,

where R1is dehydroretinol part of the antifungal compounds of the triazole type compounds containing a tertiary hydroxyl group;

or its pharmaceutically acceptable salt (here designated as "compounds of the invention").

Compounds according to the invention differ from the known compounds, as the tertiary hydroxyl group of an antifungal triazole compounds of this type was not previously subjected to functionalization.

R1preferably represents a group of formula Ia

< / BR>
where R2represents phenyl substituted by one or more halogen atoms;

R3represents H or CH3;

R3arepresents H or, together with R3may submit =CH2;

and R4represents 5 - or 6-membered nitrogen-containing heterocyclic ring, which is optionally substituted by one or more groups selected from halogen, =O, phenyl [substituted by a group selected from CN and (C6H4)-OCH2CF2CHF2] or CH= CH-(C6H4)-OCH2CF2CHF2; or phenyl substituted by one or more groups selected from halogen and methylpyrazole.

When R1represents a group of formula Ia, as defined above, R2preferably, a is 2,4-differenial and R3preferably, H is or stands.

Nitrogen-containing heterocyclic ring, which may represent or contain R4include triazolyl, pyrimidinyl and thiazolyl.

Preferred concretisation compounds, triazole, corresponding to the above groups (a)-(g) are:

(a) D-0870 (in development at Zeneca, see also example 19 European patent application 0472392); (b) fluconazole (fluconazole) (sells Pfizer, see also patent application UK 2099818); (C) example 7 of European patent application 0440372, also known as voriconazole (voriconazole); (d) example 35 patent applications in the UK 4952232; (e) compound of example 8 of the present application; (f) connection And WO 95/22973 (see page 29), originally described as compound 30 in example 27 EP 567982; and (g) ER - 30346 (see Drugs of the Future, 1996, 21(1): 20-24, Tetrahedron Letters, Vol. 37, 45, pp. 8117-8120, 1996, and European patent application 0667346, example 88).

As indicated above, the present invention relates also to a method for obtaining compounds of formula I or its pharmaceutically acceptable salt, which comprises the phosphorylation of compounds of formula II

R1OH,

where R1defined above;

and, when desirable or necessary, converting the compounds obtained into pharmaceutically acceptable salt or Vice versa.

Phosphorylation can be carried out using the following steps (1) to(3):

(1) the Interaction of the compounds of formula II above, with a compound of formula III

Raif substituted phenyl, or together with the nitrogen atom to which they are attached, they may represent the ring, such as morpholino ring; and Rcand Rdindependently, represent hydroxyamine group selected from benzyl, optionally substituted by one or more halogen atoms; obtaining Fofanova the compounds of formula IV

R1-O-P(ORc) (ORd)

where R1, Rcand Rddefined above.

The reaction can be carried out in a solvent which has no adverse effect on the reaction (e.g. methylene chloride), in the presence of a weak acid (for example, tetrazole, 5 - methyltetrazol or pyridinium hydrobromide) and, optionally, 4 - dimethylaminopyridine at room temperature or higher.

(2) the Interaction of the obtained phosphite formula IV with an oxidizing agent (for example, percolate, such as 3-chloroperoxybenzoic acid or H2O2) with a phosphate of the formula V

R1-OP(O)(ORc)(ORd)

where R1, Rcand Rddefined above. The reaction can be carried out in a solvent which has no adverse effect on the reaction (for example, methylene chloride or ethyl acetate) at a temperature below room temperature (for example, 0 - -20oC).

Alternatively, stage (1) phosphites of the formula IV can be obtained according to stage (1A) and (1B):

(1A) the interaction of the above compounds of formula II with PCl3in the presence of a base to obtain postulated intermediate compounds of formula VI

R1-O-PCl2,

where R1defined above. The reaction can be carried out in a solvent which has no adverse effect on the reaction (for example, methylene chloride or ethyl acetate) at a temperature in the range -20oC to +20oC (for example, 0oC). Suitable bases include pyridine and N-Mei.

(1B) the Interaction of the compounds of formula VI with the compound of the formula RcOH and/or RdOH (where Rcand Rddefined above), to obtain the above compounds of formula IV. This reaction is carried out without isolating the compounds of formula VI at a temperature of about room temperature.

Hydroxyamine group, which can be Rcand Rdinclude 2,6-dichlorobenzyl and 2-chloro-6-terbisil. Benzyl group can be removed by catalytic hydrogenation (for example, over a catalyst Perlman "Pearlman's catalyst or palladium-on - coal) or using bromotrimethylsilane.

If stage (3">

The above stage (3) of the method and of the intermediate compounds of formula V are additional aspects of the present invention. The compounds of formula II and III are either known or can be obtained by using known methods.

Professionals understand that in the process of synthesis of the compounds of this invention may be required to protect sensitive functional groups and the removal of protection. This can be achieved in well-known ways, for example as described in T. W. Green and P. G. M. Wuts "Protective Groups in Organic Synthesis", John Wiley and Sons Inc, 1991.

Compounds according to the invention can be used for animals, including humans, due to their pharmacological activity. In particular, the compounds can be used in the treatment or prevention of local fungal infections in humans caused by, among other organisms, Candida, Trichophyton, Microsporum or Epidermophyton or infection of the mucous membranes caused by Candida albicans (e.g., oral thrush and vaginal candidiasis). They can also be used in the treatment of fungal infections of the body, caused, for example, Candida species (e.g., Candida albicans), Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidiodes, Histoplasma or Blastomyces.

Thus, the SOG is that includes an introduction to the patient a therapeutically effective amount of the compounds according to the invention. Also proposed the use of compounds according to the invention as pharmaceutical drugs and the use of compounds according to the invention when receiving drugs to treat or prevent fungal infections.

Evaluation of antifungal activity of compounds of this invention in vitro was performed by determining the minimum inhibitory concentration (M. I. K. ), which is the concentration of tested compound in a suitable medium, in which a growth of a particular microorganism. In practice, a series of cups with agar medium, each of which includes a specific concentration of tested compound, seeded with a standard culture of, for example, Candida albicans, and then each Cup incubated for 48 hours at 37oC. Then the Cup is examined for the presence or absence of growth of fungi and note the corresponding value of the minimum inhibitory concentration, M. I. K. Others used in this test microorganisms may include Aspergillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.

Some compounds according to the invention are active in vivo, may not be active in these tests in vitro.

To evaluate and oral administration to mice, infected, for example, a strain of Candida albicans or fumigatus. The activity is based on the life span of the treated mice groups after the death of mice in the untreated group. Note the dose at which this compound provides 50% protection against the lethal action of infection (PD50). For models of infection with Aspergillus spp. the number of mice treated after the prescribed dose, allows to further assess the activity.

People can enter the connection according to the invention by themselves, but usually in a mixture with a pharmaceutically suitable carrier selected in accordance with the intended method of administration and conventional pharmaceutical practice. For example, they can be taken orally in form of tablets containing such a filler, such as starch or lactose, or in capsules or pills, by themselves or in a mixture with the filler, or in the form of elixirs, solutions or suspensions containing flavouring or tinted agents. They can be administered parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration it is best to apply them in the form of sterile aqueous solutions which may contain other substances, for example, salts or glucose in the amount of Debreceni for oral and parenteral administration to humans is from 0.01 to 20 mg/kg (single dose or divided into several times), when the introduction produce oral or parenteral. Thus tablets or capsules of these compounds contain from 5 mg to 0.5 g of active compound for administration of one compound or two or more at a time, as provided. In any case, the doctor will determine the actual dosage that best suits an individual patient, and it varies depending on age, weight and response of the individual patient. The above dosage is an example of the average case, of course, there may be some instances where the preferred ranges larger or smaller doses, and such cases are included in the scope of this invention.

Alternatively, compounds according to the invention can be introduced in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream (e.g., aqueous emulsion of polyethylene glycols or paraffin oil), or you can enter them in the composition at a concentration of from 1 to 10% ointments containing the basis of white colorless wax or soft wax together with stabilizers and preservatives that may be required.

Thus, according to yet another aspect, this invention relates to a pharmaceutical composition, moderatesevere or carrier. Of particular interest are aqueous preparations for intravenous administration.

The following examples illustrate the invention.

Example 1. 2-(2,4-Differenl)-1,3-bis(1H-1,2,4-triazole-1-yl)- 2-propertyidlist

(a) Dibenzyl 2-(2,4-differenl)-1,3-bis (1H-1,2,4-triazole - 1-yl) -2-propylphosphine

Method A (see diagram 1 at the end of the description).

A solution of 2-(2,4-differenl)1,3-bis(1H-1,2,4-triazole - 1-yl)-2-ol (also known as fluconazole, 10.0 g, a 32.6 mmol), 1H-tetrazole (6.85 g, 97.8 mmol), dibenzyldithiocarbamate) (phosphoramidite) (22,55 g, to 65.2 mmol) in methylene chloride (100 ml) was stirred at room temperature under nitrogen atmosphere for 2 hours. The mixture is then cooled to 0oC and add a solution of 3-chloroperoxybenzoic acid (13.5 g, 50-55% wt/wt, 39,1 mmol) in methylene chloride (50 ml), maintaining the temperature at 0oC. the Obtained mixture is allowed to warm to room temperature for 1 hour, then washed with aqueous sodium metabisulfite and sodium bicarbonate. After drying (MgSO4) the solvent is removed and replaced by isobutyl ketone (37 ml) and tert-butylmethylamine ether (74 ml). After pelleting at -10oC for 1 hour the product is filtered, washed with chilled on ice matila specified in the subtitle compound (of 16.05 g, 87%), so pl. 93oC.

Found: 57,12; H 4,46; N 14,85.

Calculated for C27H25F2N6O4P: 57,24; H 4,46; N 14,84% m/z 567(MH+)

1H NMR (300 MHz, CDCl3) = 4,90 (d, 2H), 4.95 points (d, 2H), of 5.05 (d, 2H), 5,19 (d, 2H), 6,58-of 6.73 (m, 2H), 6,88-to 6.95 (m, 1H), 7,20-7,30 (m, 4H), 7,32-7,38 (m, 6H), 7,80 (s, 2H), at 8.36 (s, 2H).

The way In (see diagram 2 at the end of the description).

To stir the ethyl acetate (1530 ml) is added 2-(2,4-differenl)-1,3-bis(1H-1,2,4 - triazole-1-yl)-2-ol (also known as fluconazole, 306,0 g, 1.00 mmol) and pyridine (237,3 g, 3.00 mol) before cooling to 0oC. To the reaction mixture is added dropwise phosphorus trichloride (137,4 g, 1.00 mol), keeping the temperature between 0 and 5oC, then allow the reaction mixture to warm to 15oC for 30 minutes. Then add benzyl alcohol (216 g, 2.00 mol) over 30 minutes at 15 - 20oC. after 30 minutes add the hydrogen peroxide (27,5% wt/wt in water, 373 g), keeping the temperature at 15-20oC. After 30 minutes to separate the aqueous phase and the organic phase is washed with aqueous sodium metabisulfite, diluted hydrochloric acid and water. The solvent is removed under reduced pressure and replaced by isobutyl ketone (850 ml) and tert - butylmethylamine ether (1132 ml). After pelleting at 20ooC in vacuum for 18 hours, getting mentioned in the subtitle compound (358 g, 63%). The melting point and spectroscopic data identical to the data set in method A.

(b) 2-(2,4-Differenl)-1,3-bis(1H-1,2,4 - triazole-1-yl) -2-propertyidlist (see diagram 3 in the end of the description).

Pasta connection stage (a) (9.80 g, 17.3 mmol), catalyst (5% palladium-on-coal (50% humidity, 1.0 g) and sodium hydroxide (1,38 g, 34.6 mmol) in water (26 ml) hydronaut at room temperature and a pressure of 414 kPa (60 psi = 4,219 kg/cm2) for 20 hours. The solution is filtered through a gasket from celite (trade mark) and washed with water (5 ml). Separate the toluene and cooled water phase to 0oC, then add sulfuric acid (1.70 g, 17.3 mmol). The resulting paste granularit at 0oC for 1 hour and then filtered off, washed with water (2x5 ml) and dried in vacuum at 50oC, receiving specified in the header connection (5,80 g, 87%), so pl. 223-224oC.

Found: 40,28; H 3,39; N 21,63.

Calculated for C13H13F2N6O4P: 40,43; H 3,39; N 21,76%.

1H NMR (300 MHz, DMSO) = 5,07 (d, 2H), 6,77-6,83 (m, 1H), 7,00-to 7.18 (m, 2H), of 7.75 (s, 2H), 8,53 (s, 2H).

Example 2. 2-(2,4-Differenl)-1,3-bis (1H-1,2,4-triazole-1-yl) - Rev. ) and sodium acetate (2,90 g, to 35.3 mmol) in ethanol (160 ml) and water (20 ml) hydronaut catalyst Perlman (1,00 g) at room temperature and a pressure of 345 kPa (50 psi = 3,515 kg/cm2) for 16 hours. The solution is filtered through a gasket from celite (trade mark), and the solvents removed under reduced pressure, leaving a thick syrup. It is dissolved in ethanol (100 ml) using ultrasound and heated to boiling under reflux. The resulting solution is allowed to cool down slowly and granularit for 1 hour at room temperature. The product is filtered, washed with ethanol (10 ml) and dried in vacuum at 50oC, receiving specified in the header connection (4,48 g, 59%), so pl. 160-162oC.

1H NMR (300 MHz, D2O) = 5,01 (d, 2H), 5.40 to (d, 2H), 6,60 (m, 1H), 6,79 (m, 1H), 7,11 (m, 1H), 7,63 (s, 2H), 8,68 (s, 2H).

Example 3. (2R, 3S) 2-(2,4-differenl)-3- (5-fluoro-4-pyrimidinyl-1-(1H-1,2,4-triazole-1-yl)-2-butyldihydro

(a) Dibenzyl (2R, 3S) 2-(2,4-differenl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2, 4-triazole-1-yl)-2-butylphosphate (see figure 5 at the end of the description).

A solution of (2R, 3S) 2-(2,4-differenl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazole-1-yl)-2-ol (the compound of example 7. EP 0440372, also known as voriconazole, 17.0 g, of 48.7 mmol), 4-dimethylaminopyridine (10.2 g, 83.5 mmol), 1H, tetraza is boiled under reflux for 2 hours and 16 hours at room temperature in a nitrogen atmosphere. After that, the reaction mixture is washed with hydrochloric acid and then with sodium bicarbonate, dried (MgSO4) and concentrate. The crude product (FOSFA) purified by the method of column chromatography (silica gel - 300 g, elution with hexane:ethyl acetate 3:1 to 1:1) to give a light yellow oil. It is dissolved in methylene chloride (100 ml) and cooled to -10oC, then add a solution of 3-chloroperoxybenzoic acid (14.8 g, 57% wt/wt, for 48.9 mmol) in methylene chloride (100 ml), keeping the temperature below 0oC. the Obtained mixture is allowed to warm to room temperature for 10 minutes and then washed with aqueous sodium metabisulfite and sodium bicarbonate. After drying (MgSO4) and concentration the crude product was then purified by the method of column chromatography (silica gel - 300 g, elution with ethyl acetate), obtaining mentioned in the subtitle compound as a viscous syrup (17,86 g, 60%).

m/z 610 (MH+)

1H NMR (300 MHz, CDCl3) = 1,39 (d, 3H), to 4.41 (Quartet, 1H), 4,79 (d, 2H), 4,96 (d, 2H), of 5.34 (d, 1H), of 5.40 (d, 1H), 6,59 of 6.66 (m, 1H), 6,72-PC 6.82 (m, 1H), 7,02-to 7.18 (m, 3H), 7.23 percent-7,37 (m, 8H), 7,79 (s, 1H), 8,46 (d, 1H), charged 8.52 (s, 1H), of 8.90 (d, 1H).

(b) 2R, 3S) 2-(2,4-Differenl)-3-(5-fluoro-4-pyrimidinyl-1-(1H-1,2,4-triazole-1-yl)-2-butyldihydro (see diagram 6 in the end of the description).

Races,0 g) at room temperature and a pressure of 414 kPa (60 psi = 4, 219 kg/cm2) for 16 hours. The solution is filtered through a gasket from celite (trade mark) and concentrate. The crude product is again dissolved in hot methanol (20 ml) and granularit at 0oC for 1 hour. After filtration and washing with methanol (5 ml), the product is dried in vacuum at 50oC, receiving specified in the header connection (1,72 g, 49%), so pl. 145-146oC.

1H NMR (300 MHz, DMSO) = 1,31 (d, 3H), 4,01 (Quartet, 1H), 5,31 (d, 1H), 5,42 (d, 1H), 6.90 to-6,97 (m, 1H),? 7.04 baby mortality-7,14 (m, 1H), 7,20-7,30 (m, 1H), 7,95 (s, 1H), to 8.70 (d, 1H), 8,73 (s, 1H), 8,89 (d, 1H).

Example 4. (2R, 3S) 2-(2,4-differenl)-3-(5-fluoro-4-pyrimidinyl-1-(1H-1,2,4-triazole-1-yl)-2-butyldihydro

(An alternative way of obtaining)

(a) Bis(2-chloro-6-terbisil) (2R, 3S) 2-(2,4-differenl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazole-1-yl)-2 - butylphosphate (see figure 7 at the end of the description).

A solution of (2R, 3S) 2-(2,4-differenl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazole-1-yl)-2-ol (the compound of example 7, EP 0440372, also known as voriconazole, 10.0 g, 28.6 mmol) and 1 - methylimidazole (9,40 g, 114 mmol) in methylene chloride (30 ml) cooled to 0oC, then add a solution of phosphorus trichloride (4,73 g, to 34.4 mmol) in methylene chloride (20 ml), keeping the temperature below 10oC. After 15 minutes, add a solution of 2-hornet added dropwise hydrogen peroxide (25 ml, 30% solution in water), keeping the temperature below 20oC upon cooling. After 1 hour the reaction mixture is separated, and the organic phase washed with water (I ml), dried (MgSO4) and concentrate. The obtained viscous oil granularit with tert-butylmethylamine ether (60 ml) for 2 hours at 0oC. the Product is filtered, washed with tert-butylmethylamine ether (20 ml) and dried at 50oC for 18 hours, getting mentioned in the title compound as a white crystalline solid substance (18,1 g, yield 88%), so pl. 140-141oC.

1H NMR (300 MHz, CDCl3) = 1,39 (d, 3H), 4,33 (Quartet, 1H), 5,08 (d, 1H), 5,13 (d, 1H), 5,27 (d, 1H), 5,31 (d, 1H), 5,32 (d, 1H), 5,42 (d, 1H), 6,60 to 6.75 (m, 2H), 6,92-7,07 (m, 2H), 7,11-7,37 (m, 5H), 7,81 (s, 1H), 8,44 (d, 1H), 8,61 (s, 1H), 8,91 (s, 1H).

(b) (2R, 3S) 2-(2,4-Differenl)-3-(5-fluoro-4 - pyrimidinyl-1-(1H-1,2,4-triazole-1-yl)-2-butyldihydro (see figure 8 at the end of the description).

The mixture of compounds from step (a) (50 g, 70 mmol), sodium hydroxide (8,40 g, 210 mmol) and catalyst is 5% palladium-on-coal (10 g) in toluene (450 ml) and water (150 ml) hydronaut at room temperature and a pressure of 414 kPa (60 psi = 4,219 kg/cm2) within 24 hours. The reaction mixture was filtered through celite (trade mark), and the toluene layer is separated and discarded. ablaut sulfuric acid (10.3 g, 105 mmol). After pelleting at 0oC for 1 hour the product is filtered, washed with water (60 ml) and dried in vacuum at 50oC for 16 hours, getting mentioned in the title compound (20.5 g, 68%). Data proton NMR is identical to the data obtained in example 3 (b).

Found: 44,48; H Of 3.45; N 16,19.

Calculated for C16H15F3N5O4P: 44,77; H 3,52; N TO 16.31%.

Example 5. Dehydrate (2R, 3S) 2-(2,4-differenl)-3-(5 - fluoro-4-pyrimidinyl-1-(1H-1,2,4-triazole-1-yl)-2-butyl (2 - hydroxyethyl)trimethylammoniumchloride (see chart 9 in the end of the description).

To stir the pasta from the compound of example 3(b) (214,7 g, 500 mmol) in acetone (2070 ml) is added over 10 minutes a solution of gainbegiraketa (75% wt/wt in water, 110 g, 500 mmol), filtered through a gasket from celite (trade mark) to remove insoluble products, then cooled to 20oC and granularit for 1 hour. The resulting product is collected by filtration, washed with acetone (2x250 ml) and dried at 20oC in vacuum for 18 hours, getting mentioned in the title compound (233,3 g, 74%), so pl. 114 - 115oC.

1H NMR (300 MHz, DMSO) = 1,23 (d, 3H), of 3.07 (s, 9H), to 3.38 (t, 2H), 3,60 (Quartet, 1H), 3,78 (Quartet, 2H), 5,50 (s, 2H), 6,72-to 6.80 (m, 1H), 6,94-7,02 is propoxy)styryl] -1H-1,2,4-triazole-1-yl} -3-(1H-1,2,4-triazole-1-yl)-2-propertyidlist

(a) (Dibenzyl) 2-(2,4-differenl)-1-{3- [(E)-4-(2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazole-1-yl} -3- (1H-1,2,4-triazole-1-yl) -2-propylphosphine (see figure 10 at the end of the description)

2-(2,4-Differenl)-1-{ 3-[(E)-4-(2,2,3,3 - tetrafluoropropoxy)styryl] -1H-1,2,4-triazole-1-yl} -3-(1H-1,2, 4-triazole-1-yl)propan-2-ol (racemate from example 19, EP 0472392, 475 mg, 0.88 mmol), 1H-tetrazol (185 mg, of 2.64 mmol) and dibenzyldithiocarbamate (607 mg, of 1.76 mmol) in methylene chloride (5 ml) stirred at room temperature under nitrogen atmosphere for 20 hours. The mixture is then cooled to 0oC and added dropwise hydrogen peroxide (1.0 ml, 30% solution in water), keeping the temperature below 20oC. the resulting mixture was stirred at 20oC for 30 minutes, then separate the organic layer, which is washed with water, dried (MgSO4), and the solvent is evaporated. The obtained light yellow oil purified by the method of column chromatography (silica gel, elution with ethyl acetate/hexane) to give specified in the subtitle compound as a viscous syrup (595 mg, 84%).

1H NMR (300 MHz, CDCl3) = 4,37 (t, 2H), 4,91 (d, 2H), equal to 4.97 (d, 2H), 5,02 (d, 1H), 5,07 (d, 1H), 5,16 (d, 1H), 5,18 (d, 1H), equal to 6.05 (TT, 1H), 6,59-of 6.78 (m, 2H), PC 6.82 (d, 1H), 6.90 to (d, 2H), 6,91-7,00 (m, 1H), 7,21-7,38 (m, 10H), 7,42 (d, 2H), 7,42 (d, 1H), 7,79 (s, 1H), 8,28 (s, 1H), 8,39 (s, 1H).

A solution of compound of stage (a) (298 mg, and 0.37 mmol) in methylene chloride (5 ml) cooled to 0oC and then treated with bromotrimethylsilane (254 mg, of 1.66 mmol) and pyridine (180 mg, 3.10 mmol). The resulting mixture was stirred at 0oC for 3 hours and then cooled rapidly with water (1 ml) containing sodium hydroxide (96 mg, is 2.41 mmol). The mixture is then acidified with dilute sulfuric acid and the product extracted into ethyl acetate. After washing with salt solution, the ethyl acetate phase is dried (MgSO4) and the solvent is evaporated, getting mentioned in the title compound as a pale yellow foam (202 mg, 88%).

Example 7. (2RS, 3RS)-3-(4-[4-tianfeng]thiazol-2-yl)-2-(2,4 - differenl)-1-(1H-1,2,4-triazole-1 - yl)-2-butyldihydro

(a) Dibenzyl (2RS, 3RS)-3-(4-[4-tianfeng]thiazol-2-yl)-2- (2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-butylphosphate (see figure 12 at the end of the description).

3-[4-(4-Tianfeng)thiazol-2-yl] -2- (2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (example 88, EP 0667346, 900 mg of 2.06 mmol), 1H-tetrazol (432 mg, 6,18 mmol), 4-dimethylaminopyridine (100 mg, 0.82 mmol) and dibenzyldithiocarbamate (1.42 g, 4,12 mmol) in methylene chloride (10 ml) refluxed in nitrogen atmosphere for 20 hours. The mixture is then Oh below the 20oC. the resulting mixture was stirred at 20oC for 30 minutes and then separated from the organic layer, which is washed with water, dried (MgSO4) and the solvent evaporated. The obtained light yellow oil purified by the method of column chromatography (silica gel, elution with ethyl acetate/hexane) to give specified in the subtitle compound as a viscous syrup (732 mg, 51%).

1H NMR (300 MHz, CDCl3) = 1,40 (d, 3H), of 4.38 (Quartet, 1H), 4,81-4,96 (m, 4H), of 5.40 (d, 1H), 5,43 (d, 1H), 6,62-of 6.71 (m, 1H), 6,74-PC 6.82 (m, 1H), 7,15-7,37 (m, 10H), 7,58 (s, 1H), 7.62mm (d, 2H), 7,73 (s, 1H), of 7.97 (d, 2H), 8,48 (s, 1H).

(b) (2RS, 3RS)-3-(4-[4-Tianfeng]thiazol-2-yl)-2-(2, 4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-butyldihydro (see figure 13 in the end of the description).

A solution of compound of stage (a) (310 mg, 0.44 mmol) in methylene chloride (5 ml) cooled to 0oC and then treated with bromotrimethylsilane (303 mg, to 1.98 mmol) and pyridine (215 mg, 3.7 mmol). The resulting mixture was stirred at 0oC for 3 hours and then cooled rapidly with water (1 ml) containing sodium hydroxide (115 mg, 2,87 mmol). Receives a yellow precipitate, which is marked by filtration and then share diluted sulfuric acid and methylene chloride. The organic phase is washed with brine, dried (MgSO4and you is g, 35%).

1H NMR (300 MHz, DMSO) = to 1.38 (d, 3H), 4,22 (Quartet, 1H), lower than the 5.37 (d, 1H), 5,41 (d, 1H), 6,88-6,97 (m, 1H), 7,09-7,19 (m, 1H), 7,31-7,40 (m, 1H), 7,80 (s, 1H), 7,87 (d, 2H), with 8.05 (d, 2H), 8,32 (s, IH), 8,65 (s, 1H).

Example 8. (2R, 3S)-2-(2,4-differenl)-3-[4-(1-dimethylpyrazol-5-yl) phenyl]-1-(1,2,4-triazole-1-yl)-2-buildinactiveeffect

(a) O,N-dimethyl-4-identilication acid

A solution of pyridine (104 g of 1.32 mol) in dichloromethane (150 ml) is added dropwise to a suspension of 4-identilied (251 g of 0.94 mol) and N,O-dimethylhydroxylamine (97 g of 0.94 mol) in dichloromethane (850 ml) at 0oC. the Mixture is allowed to warm to room temperature and stirred for 18 hours. The solution is evaporated under reduced pressure, the residue is dissolved in ethyl acetate (1 l) and then washed with diluted hydrochloric acid (2H, 3x400 ml) and saturated sodium bicarbonate solution (300 ml) and dried (Na2SO4). The organic extract is evaporated under reduced pressure. The residue is cleaned by distillation, obtaining mentioned in the subtitle compound (241 g, 93%) as a yellow oil, so Kip. 130oC (0.1 mm, RT. Art.), which characterize the method1H NMR.

(b) 2-(2,4-Differenl)-1-(4-itfinal)alanon

2,4-Differenziale (23,7 ml, 0,114 mol) is added dropwise to mix with the e will begin the reaction, and after that add the bromide with such a rate as to maintain gentle reflux with reflux. After 1 hour, the resulting solution of the Grignard reagent is added dropwise at -78oC to a solution of O,N-dimethyl-4 - identilication acid [see Stage (a)] (of 45.7 g of) 0.157 mol) in dry ether (300 ml), and the mixture is allowed to slowly warm to room temperature over night. Divide the mixture between saturated aqueous ammonium chloride and ethyl acetate, the organic solution is separated, dried (MgSO4) and concentrated under reduced pressure, obtaining mentioned in the title compound as a white solid (38,71 g, 69%), which is characterized by the method1H NMR spectroscopy.

(a) 2-(2,4-Differenl)-1-(4-itfinal)prop-2-Aenon

Bis(dimethylamino)methane (8,78 ml of 0.075 mol) is added dropwise to a stirred suspension of 2-(2,4 - differenl)ethanone [17,73 g, 0,04595 mol of stage (b)] in acetic anhydride (23.1 ml, 0,248 mol) at room temperature. This reaction is exothermic and the temperature of the mixture increases to 60oC. Upon completion of addition the mixture is stirred at room temperature for 35 minutes and then add ice water to hydrolyze the excess acetic anhydride. After another 30 set aside by the Russian bicarbonate, dried (MgSO4) and concentrated under reduced pressure, obtaining mentioned in the title compound as a white solid (17,03 g, 93%), which is characterized by the method1H NMR spectroscopy.

(g) 2-(2,4-Differenl)-2-(4-Ioganson) oxiran

Hydroxide designed (3,44 ml, 40% aqueous solution of 8.2 mmol) added in one portion to a solution of 2- (2,4-differenl)-1-(4-itfinal)prop-2-Aenon [37,3 g, 100,8 mmol of stage (C)] and tert-butylhydroperoxide (36,6 ml, 3 M in trimethylpentane, 109 mmol) in toluene (500 ml) at room temperature. After two hours the mixture was washed with water (2 x 500 ml), dried (MgSO4) and concentrated under reduced pressure, obtaining mentioned in the title compound as a white solid (37,46 g, 96%), which is characterized by the method1H NMR spectroscopy.

(d) (2,4-Differenl)-2-[1-(4-itfinal) ethynyl] oxiran

n-Utility (50 ml, 2.5 M in hexane, 125 mmol) is added dropwise over 10 minutes to a stirred suspension of methyltriphenylphosphonium (45,0 g, 126 mmol) in dry THF (600 ml) under nitrogen at -70oC. the Mixture is allowed to warm to -20oC for 20 minutes, then add 5 minutes a solution of 2-(2,4 - dipropenyl)-2-(4-Ioganson)oxirane [37,46 g, 97 mmol of stage (g)] in dry THF is rid of ammonia (500 ml) and the mixture is concentrated under reduced pressure. The product is extracted in ethyl acetate and the combined extract is dried (MgSO4) and concentrate under reduced pressure. The solid residue is treated with boiling hexane (3 x 500 ml), and throw the remaining solid. Hexane solutions combine, filtered through a small padding of silica gel and concentrated under reduced pressure, obtaining mentioned in the title compound as a yellow oil (34.3 g, 92%), which is characterized by the method1H NMR spectroscopy.

(e) 2-(2,4-Differenl)-3-(4-itfinal)-1-(1H-1,2,4-triazole-1-yl)-3-butene-2-ol

Sodium (1,2,4-triazole) (12,15 g, 133 mmol) are added to a solution of (2,4-differenl) -2-[1-(4-itfinal)ethynyl] oxirane [34.3 g, 89 mmol of stage (d)] in dry DMF (350 ml) in an atmosphere of nitrogen at 70oC. the Mixture is stirred for 5 hours, cooled and removed the solvent under reduced pressure. The remainder is divided between ether (800 ml) and water (2 x 500 ml). The organic solution is dried (MgSO4), filtered, and add silica gel (60-200 m, 75 g). The ether is removed under reduced pressure and the remaining solid is applied to the upper end of the column with silica gel (40-60 m, 75 g), and elute the product using hexane and an increasing amount of ethyl acetate (0-75%). Get the product as a white itfinal)-1-(1H-1,2,4-triazole-1-yl)-3-butene-2-ol](+)-3-bromocamphor-10-sulfonate

A solution of (+)-3-bromocamphor-10 - sulfonic acid (36,3 g, 0,110 mol) in IMS (40 ml) are added to a solution of the product of stage (e) (50 g, 0,110 mol) in IMS (300 ml). After priming the resulting paste granularit for 20 hours at room temperature. White solid (22 g, 0.03 mol) is collected by filtration after granulating for 1 hour at low temperature. Chiral purity, assessed by way of chiral high-performance liquid chromatography using a column Chiralcel OD and elution with ethanol/hexane [40:60], is 95% (95% EE).

(C) (R)-2-(2,4-Differenl)-3-(4-itfinal)-1-(1H-1,2,4-triazole-1-yl)-3-butene-2-ol

The product of stage (W) (206,5 g, 0.27 mol) are added to a methylene chloride (620 ml) and alkalinized 40% NaOH. The mixture is stirred for 15 minutes at room temperature and divide. The aqueous phase is re-extracted with methylene chloride (310 ml). The organic solution is washed with water (620 ml) and concentrate to a volume of 245 ml To mix the concentrate with salt added at room temperature, hexane (2450 ml) with constant speed. The resulting paste granularit at the 5oC for 1 hour. Filtration gives a white solid (117,4 g, 0.26 mol), which character-triazole-1-yl)-3-butene-2-ol

n-BuLi (1,6 H, 24,1 ml, 0.04 mol) are added to a solution of 1-methylpyrazole (3.28 g, 0.04 mol) in THF (370 ml) at -70oC, keeping the temperature below -60oC, and stirred for 30 minutes. Maintaining the temperature below -40oC, add a solution of zinc chloride (0.5 H, 77,1 ml, 0.04 mol), and then palladium-tetrakis (triphenylphosphine) (15% wt/wt, 0.9 g). Maintaining the temperature below -40oC add with constant speed the solution of stage (C) (6 g, of 0.013 mol) in THF (36 ml). The reaction mixture is allowed to warm to room temperature and then refluxed for 2 hours. After cooling to room temperature, the reaction is cooled rapidly acetic acid (12 ml) and water (120 ml), keeping the temperature below 25oC. the Reaction mixture is evaporated under reduced pressure to remove THF. The product is extracted with methylene chloride (120 ml), and then the aqueous phase is extracted with methylene chloride (50 ml). The combined organic extracts washed with water (2 x 120 ml) and concentrated, obtaining oil. To a stirred solution of the oil in ethyl acetate (100 ml) add 5-sulfosalicylic

acid (3.3 g, 0.13 mol) in IPA (10 ml). The resulting mixture is stirred for 1/2 hour at room temperature. The obtained filtered is passed solid (7.2 g, 0.01 mol). This solid is added to a methylene chloride (35 ml) and water (50 ml) and alkalinized 40% NaOH. The mixture is stirred at room temperature for 15 minutes and divide. The aqueous phase is re-extracted with methylene chloride (25 ml) and the combined organic extracts washed with water (35 ml). The organic solution is concentrated to a foam and characterize.

[]D= -25,6

Calculated for C27H25F2N6O4P: WITH 63,45; H 4,84; N 16,82%.

Found: 63,92; H A 4.86; N 16,64.

(K) (2R, 3S)-2-(2,4-Differenl)-3-[4-(1-the methylpyrazole - 5-yl)phenyl]-1-(1,2,4-triazole-1-yl)-3-butane-2-ol (see figure 14 at the end of the description)

A solution of the product of stage (I) (2.0 g, 5 mmol) in ethanol (50 ml) hydronaut at 50oC and a pressure of 50 psi (333 of kilopascal = 3,515 kg/cm2) over 5% palladium-on-coal (0.2 g) for 18 hours. Add another portion of catalyst (0.2 g) and continue to hydrogenation for 18 hours. The mixture is filtered through ArbacelTMand the filtrate is evaporated under reduced pressure. The remainder chromatographic on silica in a gradient elution with ethyl acetate/hexane/diethylamine(0:95:5 - 65:33:2). The fractions containing the desired product are pooled and evaporated under reduced pressure. The remainder of rastone solid. This solid is recrystallized from aqueous ethanol, getting mentioned in the subtitle compound (1.25 g, 62%) as a colourless solid, so pl. 144-145oC

[]D= -107 (=0,1%, CH2Cl2, 25oC)

Elemental analysis (%)

Found: 64,26; H 5,13; N 17,07.

Calculated for C27H25F2N6O4P: WITH 64,54; H 5,17; N 17,10.

[This compound disclosed as example 67 in co-filed international patent application PCT/ER/02470].

(l) (Dibenzyl) (2R, 3S)-2-(2,4-differenl) -3-[4-(1-the methylpyrazole-5-yl)phenyl] -1-(1,2,4-triazole-1-yl)-2-butylphosphate (see figure 15 in the end of the description).

A solution of product from step (K) (2.0 g, 4.4 mmol), dibenzyldithiocarbamate (2.28 g, 6.6 mmol), tetrazole (0,92 g, 13,2 mmol) and 4 - dimethylaminopyridine (50 mg) in dichloromethane (30 ml) heated to boiling under reflux for 13 hours. The reaction mixture was cooled (0oC) and add metallocarborane acid (1.52 g, 8,8 mmol). The solution was stirred at 0oC for one hour, then allowed to warm to room temperature. The reaction mixture was washed with aqueous solution of sodium sulfite (10%, 30 ml), saturated sodium bicarbonate solution (30 ml) and solely the oil. Cleaning method column chromatography (silica gel 45 g, gradient elution from toluene to 3.5% of diethylamine in toluene) to give the desired product as a colourless oil (0.8 g, 27%), m/z 671 (M++1).

1H NMR (CDCl3) = a 1.3 (d, 3H), and 3.8 (s, 3H), 3,85 (Quartet, 1H), 4,8 (m, 2H), 4,9 (m, 2H), and 5.2 (s, 2H), and 6.25 (s, 1H), 6,6 (m, 1H), 6,8 (m, 1H), 7,05 (m, 1H), 7,15 (m, 2H), 7,2-7,35 (m, 12H), and 7.5 (s, 1H), and 7.8 (s, 1H), 8,23 (s, 1H).

(m) (2R, 3S)-2-(2,4-Differenl)-3-[4-(1-the methylpyrazole-5-yl) phenyl] -1-(1,2,4-triazole-1-yl)-2-buildinactiveeffect (see figure 16 in the end of the description).

A suspension of the product of stage (l) (0.5 g, 0.75 mmol) and sodium acetate (0.14 g, of 1.65 mmol) in ethanol (20 ml) hydronaut over 5% palladium-on-coal (75 mg) at room temperature and pressure 333 kPa (50 psi = 3,515 kg/cm2) within 24 hours. Thin layer chromatography shows a partial completion of the reaction, and the catalyst is filtered off through a gasket filter Arbacel (trade mark). Then add the catalyst Perlman (Perlman''s catalyst) and continue hydrogenation within 72 hours. The catalyst is filtered off through a gasket Arbacel, and remove the solvent in vacuo. The residue is dissolved in dichloromethane (20 ml), and filtered through a gasket filter (Hiflow, trademark) to remove excess sodium acetate. Restorage white solid (0,250 g, 68%).

Found: 46,66; H To 4.87; N 11,82.

Calculated for C22H22F2N5Na2O4P 0,09 Et2O: 46,62; H 4,36; N 12,16%.

1H NMR (DMSO) = 1,2 (d, 3H), 3,75 (Quartet, 1H), and 3.8 (s, 3H), 5,1, 5,5 (AB system, 2H), and 6.3 (s, 1H), 6,9 (m, 1H), 7.2V, 7.4V (AB system, 4H), and 6.6 (m, 1H), 6,8 (m, 1H), 7,05 (m, 1H), 7,15 (m, 2H), and 7.4 (m, 3H), 7,45 (m, 1H), and 7.6 (s, 1H), and 9.1 (s, 1H).

Example 9

Compare the solubility of the compounds of examples 1, 3 and 8 (in the form of their Dimitrievich salts) with the solubility of the corresponding source (nefosfaurilirovanna) compounds (in the form of free bases). The results are presented in table. 1 (see the end of the description).

Example 10

Aqueous preparations for intravenous injection are presented in table. 2 at the end of the description.

Studies demonstrating biological equivalence injectable in a small volume procarcinogen drug phosphate fluconazole and introduced by infusion of a large volume of fluconazole.

The objects of study and planning of the experiment

The main object of the study was to investigate the pharmacokinetics of fluconazole contained in the dosage form in the form of a bolus intravenous injection of 1000 mg (equivalent to 800 mg of fluconazole) prolekarstvom the research was to compare the safety and tolerance of intravenous bolus procarcinogen drug phosphate fluconazole and intravenous infusion of fluconazole.

This was a randomized, double-repeated blind research method with twice repeated simulation of the way, with the introduction of a single dose, including two period, crossover study with a period of 14 days between the introduction of the medicine to flush drugs from the body.

Subjects

The study involved 24 healthy men (aged 18 to 42 years; weight from 58,7 up to 96.9 kg). All involved in the investigation were representatives of the white race. Five of them were smokers.

Medication

Proletarskiy the phosphate drug fluconazole was provided in the form of solutions of 100 mg/ml (euivalent 80 mg/ml of fluconazole) in 10 ml ampoules (see example 10 of this application). Placebo was supplied in 10 ml vials of 0.9% sodium chloride solution.

Fluconazole was provided in the form of a solution of 2 mg/ml in 100 ml tubes. Placebo for fluconazole was provided in the form of a 0.9% solution of sodium chloride in 500 ml packages. Fluconazole or placebo aseptic method was transferred into a 500 ml infusion bags used for injection.

Twice repeated simulation of the way included the introduction through the same permanent cannula (1) bolus injection prolekarstvom infusion; or (2) bolus injections of placebo for procarcinogen funds phosphate fluconazole immediately after the introduction of 800 mg of fluconazole by continuous infusion for 4 hours.

pharmacokinetic results

Individual and average pharmacokinetic profiles of fluconazole, followed by the introduction procarcinogen preparation of phosphate of fluconazole and fluconazole is shown in Fig. 1 and 2, respectively. Brief description of pharmacokinetic parameters of fluconazole are presented in table. 1.

The geometric mean of the bioavailability of fluconazole from procarcinogen funds phosphate fluconazole was 97% (90% CI 95%-99%). The concentration of fluconazole in plasma was initially higher after intravenous bolus injection procarcinogen funds phosphate fluconazole compared with intravenous infusion of fluconazole, but the maximum concentration (CMAX) fluconazole was higher after infusion of fluconazole. The geometric mean value of fluconazoleMAXafter the introduction procarcinogen funds phosphate of fluconazole than with fluconazole was 86% (90% CI 84%-88%). The average time required for maximalizovalo 3 hours (from 0.5 to 6 hours). The ultimate half-life of the organism (t1/2and the average residence time in the body (MRT) of fluconazole were the same after 2 treatments.

Conclusions

The bioavailability of fluconazole from procarcinogen tools - phosphate fluconazole was 97% (90% CI 95%-99%). Therefore, the equivalent systemic exposure of fluconazole can be obtained by bolus intravenous injection procarcinogen funds phosphate of fluconazole. Bolus intravenous injection of 1000 mg procarcinogen of phosphate drug fluconazole is well tolerated in comparison with intravenous infusion of 800 mg of fluconazole, with the same profile of side effects. Next, see table. 3 at the end of the description.

1. Derivatives of triazole of the General formula I

R1-OP(O)(OH)2(I)

where R1represents a group of formula Ia

< / BR>
where R2represents phenyl substituted by two halogen atoms;

R3represents N or CH3;

R3ais N;

R4is triazolyl, optionally substituted by a group CH= CH(C6H4)OCH2CF2CHF2; pyrimidinyl substituted with one halogen atom; phenyl substituted by methylpyrazolo; thiazolyl, Sames the ASS="ptx2">

2. Connection on p. 1, where R2is 2,4-differenial.

3. Connection under item 1 or 2, where R4constitutes or contains triazolyl, pyrimidinyl or thiazolidine group.

4. The compound according to any one of the preceding paragraphs, which is: 2-(2,4-differenl)-1,3-bis-(1,2,4-triaal-1-yl)-2-propertyidlist, or (2R, 3S)-2-(2,4-differenl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanedisulfonate, or their pharmaceutically acceptable salts.

5. Pharmaceutical composition having anti-fungal activity, containing triazole derivative in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, characterized in that as a derivative of triazole it contains an effective amount of the triazole derivative of the General formula I under item 1 or its pharmaceutically acceptable salt.

6. The compound of formula I under item 1 or its pharmaceutically acceptable salt as a medicine to treat or prevent fungal infections.

7. Method for the treatment or prevention of fungal infections, which consists in introducing the compound of formula I under item 1 or its pharmaceutically acceptable salt in need is almost acceptable salt, includes the following stages: a) phosphorylation of compounds of formula II

R'-OH, II

where R' has the meanings given in paragraph 1,

the compound of the formula III

RaRbN-P(ORc)(ORd), III

where Raand Rbindependently represent C1-C6alkyl, phenyl, substituted phenyl, or together with the N atom to which they are attached, may represent a ring;

Rcand Rdindependently represents hydroxyamino group

obtaining the compounds of formula IV

R1-OP(ORc)(ORd), IV

where R1, Rcand Rdhave the specified values;

b) oxidation of the compounds of formula IV to obtain the phosphate compounds of formula V

R1-OP(O)(ORc)(ORd), V

where R1, Rcand Rdhave the specified values;

(C) removing hydroxyamine groups Rcand Rdin the compound of formula V to obtain the compounds of formula I and (d) optional conversion of the compounds of formula I, its pharmaceutically acceptable salt.

9. The method of obtaining the compounds of formula I according to any one of paragraphs.1-4 or its pharmaceutically acceptable salt, comprising the following stages: a) compound of formula II

R'-OH, II
R1-OPCl2VI

where R1matter mentioned above,

with the subsequent reaction with the compound of the formula

RcHE and/or RdOH,

where Rcand Rddefined above,

obtaining the compounds of formula IV

R1-OP(ORc)(ORd), IV

where R1, Rcand Rdhave the specified values;

b) oxidation of the compounds of formula IV to obtain the phosphate compounds of formula V

R1-OP(O)(ORc)(ORd), V

where R1, Rcand Rdhave the specified values;

c) removing hydroxyamine groups Rcand Rdin the compound of formula V to obtain the compounds of formula I and (d) optional conversion of the compounds of formula I, its pharmaceutically acceptable salt.

10. The compound of formula V

R1-OP(O)(ORc)(ORd), V

where R1defined in paragraph 1,

Rcand Rdindependently represents hydroxyamine group selected from benzyl, optionally substituted by one or more halogen atoms.

 

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